The present invention relates to a novel method of inducing diuresis in mammals. This invention further provides novel compounds to be used in this method. In particular, the present invention relates to the use of certain 2,6-diaryl-4-pyridinecarboxylic acids as diuretics.
Diuretics are agents which increase the rate of urine formation. In particular, they increase net renal excretion of solute (e.g., electrolytes such as sodium, potassium, chloride, and bicarbonate ions) and water. They are useful for a variety of pharmacological purposes. The most important such purposes is the treatment of edema, i.e., the presence of excess fluid in the intercellular tissue spaces of the body. Diuretics are also useful in the treatment of certain types of hypertension.
In a healthy individual, a relatively constant volume of extracellular fluid is maintained. Thus, sodium and water excretion by the kidney is adjusted according to the variations in salt and water intake. In certain disease states, however, the rate of excretion of sodium and water may be so reduced that even a small daily intake of sodium and water is retained and this leads to a progressive expansion of the volume of extracellular fluid. Disease states which cause the rate of excretion of sodium and water to be reduced include congestive heart failure, cirrhosis of the liver, and various renal diseases. As a rule, untreated edematous states are characterized by expansion of extracellular fluid volume without distortion of the composition of that fluid.
Thus, since the goal of diuretic therapy is the mobilization of edematous fluid in such a manner that the extracellular fluid is restored toward normal, in terms of both volume and composition, it would be advantageous to employ diuretic agents which have little or no effect on electrolyte concentrations.
A number of diuretic agents are known. These include mercurial diuretics, thiazide diuretics, "loop" diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. Other diuretics include furosemide, ethacrynic acid, spironolactone, and triamterene. See Goth Medical Pharmacology, 9th Edition (1978), and Goodman and Gillman, The Pharmacological Basis of Therapeutics, 5th Edition (1971).
One problem with the prior art diuretic agents is that generally the more potent the diuretic, the more it tends to distort the electrolyte composition of the extracellular fluid. Spironolactone and triamterene conserve potassium, but they are not very potent when used alone. The mercurial diuretics also do not greatly effect the potassium balance, but they must be administered intramuscularly. Mercurial dicuretics have many undesirable side effects. They can cause an accumulation of mercury, which is highly toxic.
The 2,6-diaryl-pyridinecarboxylic acids of the present invention are trivially named as bis-aryl-isonicotinic acids. Some of the isonicotinic acids of the present invention are known and have been disclosed as useful as intermediates in the production of anti-malarial compounds. See M. P. LaMontagne, et al., J. Med. Chem. 16:1040-1041 (1973); P. Blumbergs et al., J. Med. Chem. 15:808-812 (1972); A. Markovac, J. Med. Chem. 15:918-922 (1972); and U.S. Pat. Nos. 3,753,997; 3,763,148; and 3,600,396.
The compounds employed in the method of the present invention are derivatives of 2,6-diphenylisonicotinic acid, which has the chemical structure and numbering as shown in Formula I. This compound is named 2,6-diphenyl-4-pyridinecarboxylic acid using the Chemical Abstracts numbering system. (See Naming and Indexing of Chemical Substances for Chemical Abstracts During the 9th Collective Period, a reprint of Section 4 from the Chemical Abstracts Vol. 76 Index Guide (1972-1976).)